Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, Indiana.
Department of Anatomy and Cell Biology, Indiana University School of Medicine , Indianapolis, Indiana.
Am J Physiol Endocrinol Metab. 2019 May 1;316(5):E749-E772. doi: 10.1152/ajpendo.00343.2018. Epub 2019 Jan 15.
A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor nuclear matrix protein 4 (, , , ) respond to several classes of osteoporosis drugs with enhanced bone formation compared with wild-type (WT) animals. mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyperanabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that MSPCs exhibited an enhanced capacity for glycolytic conversion: a key step in bone anabolism. cells showed elevated collagen translation and secretion. The expression of matrix genes that contribute to bone material-level mechanical properties was elevated in cells, an observation that was supported by biomechanical testing of bone samples from and WT mice. We conclude that loss of increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality.
骨质疏松症治疗的目标是用结构健全的组织来恢复丢失的骨骼。与野生型（WT）动物相比，缺乏转录因子核基质蛋白 4（NMP4）的小鼠对几类骨质疏松症药物的反应是骨形成增强。间充质干细胞/祖细胞（MSPCs）在成骨细胞分化过程中表现出加速和增强的矿化。为了解释这种超代谢表型的机制，我们对 WT 和 NMP4 MSPCs 在成骨过程中的 RNA 测序以及分子和细胞分析进行了研究，以确定与基质产生增加相关的途径和机制。我们确定 NMP4 在成骨分化过程中对转录组有广泛的影响，有助于超过 5000 个基因的表达。通过分析细胞代谢、蛋白质合成和分泌以及骨材料特性，对转录组数据进行表型锚定，为假设检验提供了依据。通过对 NMP4 MSPCs 的糖酵解转化能力、胶原翻译和分泌能力以及对骨材料力学性能有贡献的基质基因表达的研究，证实了这一假说。细胞中的实验表明，NMP4 MSPCs 表现出增强的糖酵解转化能力：这是骨合成代谢的关键步骤。NMP4 细胞表现出更高的胶原蛋白翻译和分泌能力。对 NMP4 和 WT 小鼠的骨样本进行生物力学测试，支持了骨材料水平力学性能相关基质基因表达升高的观察结果。我们得出的结论是，NMP4 的缺失增加了代谢转换时糖酵解的幅度，这为成骨细胞向基质超分泌者的转化提供了动力，从而产生更多的骨，改善了内在质量。
